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Abstract:

An apparatus for treating the brain comprises an implantable fluid
exchange device coupled to a control unit to periodically alternate a
delivery of a therapeutic agent with a removal of cerebrospinal fluid
from a cranial subarachnoid space to prevent local inflammatory
host-products from blocking a transmeningeal diffusion of the therapeutic
agents into the cerebral cortex and thereby allow an effective treatment
of cerebral cortical disorders by the delivery therapeutic agents.

Claims:

1. An implantable fluid exchange device configured to periodically
alternate a delivery of a therapeutic agent with a removal of
cerebrospinal fluid from a cranial subarachnoid space to prevent local
inflammatory host-products from blocking a transmeningeal diffusion of
the therapeutic agents into the cerebral cortex and thereby allow an
effective treatment of cerebral cortical disorders by the delivery
therapeutic agents.

2. The fluid exchange device of claim 1, further comprising an interface
configured for placement in the cranial subarachnoid space and coupled to
a control unit configured for periodically moving fluids containing the
therapeutic agent into the interface and fluids with cerebrospinal fluid
and the inflammatory host-products out of the interface.

3. The fluid exchange device of claim 2, wherein the interface comprises
one fluid exchange port with at least two physically separated openings,
wherein one of the openings is continuous with a tube carrying the
therapeutic agent from the control unit into the fluid exchange port and
wherein the other one of the openings is continuous with another tube
carrying cerebrospinal fluid from the fluid exchange port to the control
unit.

4. The fluid exchange device of claim 3, further comprising a seal
configured to surround the fluid exchange port to prevent fluid delivered
thereto via the fluid exchange port from leaking out of an area
encompassed by the seal.

5. The fluid exchange device of claim 1, further comprising at least one
neurochemical sensor providing feedback on the efficacy of the delivered
therapeutic agent.

6. The fluid exchange device of claim 1, further comprising a
physiological recording electrode providing feedback on the efficacy of
the delivered therapeutic agent.

7. The fluid exchange device of claim 6, wherein the electrode is a EEG
electrode configured to record field potentials of approximately 0.1 to
500 Hz.

9. The fluid exchange device of claim 8, wherein each of the additional
fluid exchange ports comprises at least two physically separated
openings, wherein one of the openings is continuous with a tube carrying
the therapeutic agent from the control unit into the fluid exchange port
and wherein the other one of the openings is continuous with another tube
carrying cerebrospinal fluid from the fluid exchange port to the control
unit.

10. The fluid exchange device of claim 3, further comprising a control
unit configured and dimensioned for implantation at a site remote from
the interface, the control unit including a microprocessor-controlled
dual pump connected to the tubes of the two physically separated openings
to control delivery of the first fluid to and withdrawal of fluid from
the first target area.

11. The fluid exchange device of claim 10, wherein the pump is coupled to
a supply reservoir including a supply of the therapeutic agent and a
collection reservoir for receiving the withdrawn cerebrospinal fluid and
inflammatory host products, the supply reservoir being connected to a
refilling subcutaneous port configured to permit access to the first
supply reservoir by a percutaneously inserted refilling device first
fluid and the collection reservoir being connected to a fluid removal
subcutaneous port configured to permit access to the collection reservoir
by a percutaneously inserted fluid removal device.

12. The fluid exchange device of claim 3, further comprising a control
unit configured and dimensioned for implantation at a site approximately
30 centimeters from the interface, the control unit including a
microprocessor-controlled dual pump connected to the tubes of the two
physically separated openings to control delivery of the first fluid to
and withdrawal of fluid from the first target area.

13. The fluid exchange device of claim 10, wherein the microprocessor is
programmed to detect and process one or more of neurochemical,
physiological and EEG signals from the fluid exchange device.

14. The fluid exchange device of claim 10, wherein the microprocessor is
programmed to direct the pump to alternate fluid delivery and fluid
removal to and from the fluid exchange device in a periodic manner.

15. An apparatus for treating the brain, comprising: a fluid exchange
device sized and shaped for placement in a first target area of one of a
subdural and a target subarachnoid space, the fluid exchange device
including a first lumen extending to a first inlet port at a distal end
of the first lumen and a second lumen extending to a first outlet port at
a distal end of the second lumen; and a fluid delivery/withdrawal
apparatus delivering a first fluid to the first target area via the first
lumen and the first inlet port and removing fluid from the first target
area via the second lumen and the first outlet port, the fluid
delivery/withdrawal apparatus periodically supplying the first fluid to
and removing fluid from the first target area in volumes and at times
selected to prevent the aggregation of inflammatory and host response
materials produced by the body.

16. The apparatus of claim 15, wherein the fluid exchange device is sized
and shaped to be positioned between an arachnoid mater and a pia mater of
the brain.

17. The apparatus of claim 15, further comprising a first sensor mounted
on the first fluid exchange device and configured to monitor neurological
data without penetrating a cerebral cortical neural layer of the brain.

18. The apparatus of claim 15, further comprising a second fluid
delivery/withdrawal apparatus delivering the first fluid to a second
target area via a third lumen and including a second inlet port, the
second fluid delivery/withdrawal apparatus periodically supplying the
first fluid to and removing fluid from the second target area in volumes
and at times selected to prevent the aggregation of inflammatory and host
response materials produced by the body.

19. The apparatus of claim 16, further comprising a first seal
surrounding the first inlet and outlet ports, the first seal configured,
in a sealing configuration, to engage tissue surrounding the first inlet
and outlet ports to retain fluids in the first target area.

20. The apparatus of claim 19, further comprising a plurality of seals,
each surrounding a corresponding pair of inlet and outlet ports, each
seal being configured so that, in a sealing configuration, it engages
tissue surrounding the corresponding pair of inlet and outlet ports to
retain fluids in a corresponding target area to be treated by the
corresponding pair of inlet and outlet ports.

21. The apparatus of claim 20, wherein the seals are arranged in one of a
grid and a longitudinal strip.

22. The apparatus of claim 20, wherein the fluid exchange device includes
a first part positioned within the subdural space and a second part
positioned within the subarachnoid space, the first inlet and outlet
ports being located on the first part and a further one of the pairs of
inlet and outlet ports being located on the second part.

23. The apparatus of claim 15, wherein the first fluid
delivery/withdrawal apparatus further comprises a third inlet port
coupled via a fourth lumen to a first fluid collection reservoir.

24. The apparatus of claim 23, wherein the first fluid
delivery/withdrawal apparatus further comprises a third outlet port
configured coupled to a source of a second fluid to a second target area.

25. The apparatus of claim 15, wherein the first fluid is a solution
comprising one or more of genes, peptides, proteins, cells and a flushing
fluid solution.

26. The apparatus of claim 15, further comprising a pump configured and
dimensioned for implantation at a site remote from distal ends of the
first and second lumens, the pump being connected to proximal ends of the
first and second lumens to control delivery of the first fluid to and
withdrawal of fluid from the first target area.

27. The apparatus of claim 26, wherein the pump and the first fluid
exchange device are formed as a single unit implantable in a cranium.

28. The apparatus of claim 26, wherein the pump is coupled to a first
supply reservoir including a supply of the first fluid and to the first
collection reservoir.

29. The apparatus of claim 28, wherein the pump is coupled to a second
supply reservoir including a supply of the second fluid.

30. The apparatus of claim 28, further comprising a refilling
subcutaneous port configured to permit access to the first supply
reservoir by a percutaneously inserted refilling device.

31. The apparatus of claim 26, further comprising first and second flow
sensors provided on connections to the first and second fluid lumens to
monitor fluid flow therethrough.

32. The apparatus of claim 28, further comprising a fluid removal
subcutaneous port configured to permit access to the first collection
reservoir by a percutaneously inserted fluid removal device.

33. The apparatus of claim 32, wherein the pump further is coupled to a
second collection reservoir for receiving withdrawn fluid.

34. A method for treating the brain, comprising: implanting a fluid
exchange device in a first target area of one of a subdural and a
subarachnoid space, the fluid exchange device including a first lumen
extending from a proximal end to a first inlet port at a distal end
thereof and a second lumen extending from a proximal end to a first
outlet port at a distal end thereof; implanting a fluid
delivery/withdrawal device at a location in the body remote from the
first target area, the fluid delivery/withdrawal device being coupled to
the proximal ends of the first and second lumens, the fluid
delivery/withdrawal device being coupled to a source of a first fluid for
delivery to the first target area; and operating a fluid
delivery/withdrawal device to periodically supply the first fluid to the
first target area via the first lumen and withdraw fluid from the first
target area in volumes and at times selected to prevent the aggregation
of inflammatory and host response materials produced by the body.

35. The method of claim 34, wherein amounts of fluid withdrawn from the
first target area correspond to amounts supplied thereto to maintain a
desired level of fluid within the first target area.

36. The method of claim 34, further comprising the step of controlling a
rate and volume of delivery of the first fluid and withdrawal of fluid
from the first target area by a microcontroller in a control unit
implanted remote from the first target area.

37. The method of claim 36, further comprising the step of wirelessly
programming the control unit to adjust the rate and volume of fluid
delivery and withdrawal.

38. The method of claim 36, wherein the control unit is configured to
automatically adjust the rate and volume of fluid delivery and withdrawal
in response to a detection of one of predetermined electrophysiological
and neurochemical signals received from sensors provided on a distal end
of the fluid exchange device.

39. The method of claim 34, wherein the step of fluid withdrawal is
performed one of ten minutes after the step of the first fluid delivery
and less than one minute after the step of the first fluid delivery.

40. The method of claim 39, further comprising the step of supplying a
predetermined dosage of the first fluid to the first target area via the
first inlet port immediately after withdrawal of fluid therefrom.

41. The method of claim 34, further comprising the step of refilling a
first drug reservoir containing a supply of the first fluid via a
subcutaneous refilling port.

42. The method of claim 34, wherein withdrawn fluid is stored in a first
collection reservoir, the method further comprising the step of
permanently removing fluid from the collection reservoir via a fluid
removal subcutaneous port connected thereto.

Description:

FIELD OF THE INVENTION

[0001] This invention generally relates to the delivery of drugs and other
therapeutic agents directly into the brain via intracranially implanted
devices, and particularly relates to effective transmeningeal drug and
therapeutic agent delivery for the treatment of neurological disorders
with focal cerebral cortical pathology.

BACKGROUND

[0002] Transmeningeal delivery refers to a treatment modality in which
drugs and other therapeutic agents are delivered into a cranial
subarachnoid space to allow them to diffuse through the pia mater into an
underlying, diseased cerebral cortical area and thereby correct abnormal
neural functions in that cortical area. Neurological disorders with focal
cerebral cortical pathology include various forms of focal epilepsy,
stroke, traumatic brain injury, and tumors. Although drug delivery
directly into the subdural/subarachnoid space of the spinal cord
("intrathecal administration") is widely used in clinical practice for
pain relief in obstetric anesthesia, as well as in lower abdominal,
urogenital, rectal and lower extremity surgical procedures, the
subdural/subarachnoid compartment of the brain is currently not utilized
for therapeutic purposes, such as for the treatment of cerebral cortical
disorders. This is due to a lack of appropriate devices which are both
implantable in the subdural/subarachnoid space without causing
significant damage to neural tissue and can also perform localized
medication delivery for long periods without an eventual clogging or
obstruction in their delivery systems rendering them incapable of
functioning as intended. Current experimental or clinically used
cannulas, catheters or drug-releasing polymers share the same common
problem that bedevils their use. This problem is the induction of
inflammatory host responses that encapsulate or clog the implant,
preventing its ability to maintain constant, or at least sufficient,
therapeutic agent delivery with consequent therapeutic effects. The
inflammatory host response is mediated by cells, such as mast cells,
macrophages, lymphocytes, fibroblasts and other cellular elements, and by
molecules, such as various collagen, elastin, proteoglycans, adhesive
glycoproteins and other molecules, which, together accumulate and
aggregate, forming a fibrous, gelatinous layer over the dorsal surface of
the cerebral cortex and its covering pia mater within 2-3 weeks. This
layer of newly generated connective tissue forms a lasting barrier to
drugs or other medications and therapeutic agents delivered into the
subarachnoid space, effectively blocking their transmeningeal influx into
the cortical tissue. As a consequence, presently used or experimental
needles, cannulas, catheters, or drug-releasing polymers cannot provide
treatment for cerebral cortical disorders for periods longer than 2-3
weeks. This forbids their implantation for the treatment of chronic
cerebral cortical disorders, the treatment of which requires persistent
treatment over a period of several month or years.

SUMMARY OF THE INVENTION

[0003] The present invention relates to a system and method for treating
cerebral cortical disorders via a fluid exchange device sized and shaped
for placement in a space separating the cranial dura and pia maters. The
exemplary system of the present invention includes at least one fluid
exchange port equipped with a leakage-preventing seal and at least two
tubes, wherein one tube is configured to deliver fluid with therapeutic
solutes and wherein the other tube is configured to remove cerebrospinal
fluid (CSF) with accumulated inflammatory tissue reaction products from
the area of the port, thereby preventing clogging of the fluid delivery
tube and therefore allowing effective diffusion of the delivered
therapeutic solutes into the treated cerebral cortical region.

[0004] The present invention also relates to a method for using the
aforementioned fluid exchange device effectively by alternating the fluid
delivery/fluid removal cycles with intervals that prevent the aggregation
of inflammatory products in the fluid exchange ports, provide effective
diffusion of the therapeutic solutes into the treated cortex, and keep
the treated cortical surface bathed in a physiological mixture of natural
and artificial cerebrospinal fluids.

BRIEF DESCRIPTION OF THE DRAWINGS

[0005]FIG. 1 shows an exemplary embodiment of a subdural/subarachnoid
system according to the present invention;

[0006] FIG. 2 shows a detailed view of a control unit of the system of
FIG. 1;

[0007]FIG. 3 shows a detailed view of the subdural/subarachnoid strip of
FIG. 1;

[0008]FIG. 4 illustrates a first exemplary method for generating periodic
fluid delivery and fluid removal cycles according to the present
invention;

[0009]FIG. 5 illustrates a second exemplary method for generating
periodic fluid delivery and fluid removal cycles according to the present
invention;

[0010]FIG. 6 depicts experimental results obtained in an implanted
subdural/subarachnoid sheet body subjected to the periodic fluid delivery
and fluid-removal cycles of FIG. 4 prior to the delivery and removal of
predetermined fluids;

[0011]FIG. 7 depicts experimental results obtained in an implanted
subdural/subarachnoid sheet body subjected to the periodic fluid delivery
and fluid-removal cycles of FIG. 4 recorded 12 minutes after the delivery
of a first predetermined fluid; and

[0012]FIG. 8 depicts experimental results obtained in an implanted
subdural/subarachnoid sheet body subjected to the periodic fluid delivery
and fluid-removal cycles of FIG. 4 recorded 2 minutes after the delivery
of a second predetermined fluid.

DETAILED DESCRIPTION

[0013] The present invention may be further understood with reference to
the following description and the related appended drawings, wherein like
elements are provided with the same reference numerals. The present
invention describes a system combining pharmacological and
electrophysiological instruments for the treatment of brain disorders. A
system in accordance with the present invention includes a
subdural/subarachnoid therapeutic agent fluid exchange device for
implantation in a subdural/subarachnoid space. The device is formed as a
thin sheet of flexible biocompatible material suitable for placement in
the cranial subdural/subarachnoid space and incorporates multiple sealed
fluid-exchange ports, with each port having at least one inlet for local
transmeningeal fluid delivery and at least one outlet for local fluid
removal. At least some of the inlet and outlet ports further comprise
electrode and/or neurochemical sensor contacts to provide feedback on the
local cortical effects of the performed fluid deliveries and removals
without penetrating into cerebral cortical neural layers. The device of
the present invention further comprises a central control unit
integrating a mini-pump configured to control a flow of fluids into and
out of the subdural/subarachnoid space. The control unit is equipped with
miniature subcutaneous ports accessible from the outside the body, for
both periodic refilling of the delivery fluids and periodic elimination
of the removed fluids therefrom. The mini-pump and control unit are
configured to perform both fluid delivery to and fluid removal from the
subarachnoid space in an alternating manner to prevent the obstruction of
fluid exchange ports of the delivery device while also preventing
accumulation and aggregation of local inflammatory and host-response
cells and molecules effectively cleansing lumens of the fluid exchange
device and creating a condition whereby drugs and other therapeutic
agents delivered through the fluid exchange ports can diffuse
transmeningally into the underlying cerebral cortical tissue to exert
therapeutic action without hindrance. The exemplary embodiment of the
present invention produces a long-term stream of fluid delivery and fluid
removal cycles in the subdural/subarachnoid space for the treatment of
neurological disorders with cerebral cortical pathology, such as focal
neocortical epilepsy and some types of stroke, brain injury and brain
tumor. It is noted that although the present invention has been described
with respect to the treatment of a few neurological conditions, the
exemplary systems and methods may also be applied for the treatment of
any other neurological abnormalities without deviating from the spirit
and scope of the present invention.

[0014] As shown in FIGS. 1-3, a system 100 according to the present
invention comprises a subdural/subarachnoid sheet body 102 implantable
into a subdural/subarachnoid space 30 between an arachnoid mater 10 and a
pia mater 20 of a cerebral cortex 50. As understood by those skilled in
the art the subdural/subarachnoid space 30 is filled with cerebrospinal
fluid ("CSF"). The subdural/subarachnoid sheet body 102 is formed as a
flexible sheet of bio-compatible material (e.g., silicone) having a
thickness smaller than approximately 3 mm. The sheet body 102 comprises a
cortical surface 104 configured to be positioned adjacent the pia mater
20 and a dorsal surface 106 configured to be positioned against the
arachnoid mater 10 when implanted in the cerebral cortex 50 in an
operative configuration. The shape of the sheet 102 of flexible
bio-compatible material can be one of a strip and a grid. Furthermore,
although the present embodiment is described with a single
subdural/subarachnoid sheet body 102 implanted in the cerebral cortex, a
single or multiple strips and/or grids may be used in any combination and
number, depending on the size and location of the target area such as a
cerebral cortical seizure focus, infarct, tumor, area of traumatic
injury, as those skilled in the art will understand. Furthermore, the
single or plurality of strips and/or grids may be placed either in the
subarachnoid space only or in both the subdural and subarachnoid spaces,
as those skilled in the art will understand.

[0015] A plurality of sealing rings 108 is provided on the cortical
surface 104. The sealing rings 108 are configured and dimensioned to
contact the pia mater 20 covering a cerebral cortical surface 40 in a
manner so that a series of gaps 110 is provided between the pia mater 20
and the cortical surface 104 of the sheet body 102. The gaps 110 are
therefore enclosed in a substantially fluid-tight manner so that fluid
introduced by the system 100 into each of the gaps 110 is maintained in a
target area and is substantially prevented from spilling over to adjacent
portions of the cerebral cortex 50 (e.g., non-targeted cortical areas).
In the embodiment shown, three rings 108 are provided, creating two
separate gaps 110. It is noted however, that any other number of gaps 110
sealing by sealing rings 108 may be integrated within the
subdural/subarachnoid system 100 without deviating from the spirit and
scope of the present invention.

[0016] As shown in FIGS. 1 and 3, a fluid exchange port 111 comprising
inlet and outlet tubes 112, 114 opens into each of the gaps 110. The
inlet tube 112 delivers a fluid such as a therapeutic drug solution. In
an exemplary embodiment, the therapeutic drug solution may be one or more
of a drug solution, brain-derived natural molecules, flushing solutions
(e.g., saline, etc.), peptides, proteins, genes, cells, etc. The
therapeutic drug solution may contain only a single compound or a
combination of two or more compounds including anti-inflammatory drugs
and other agents that prevent the generation, accumulation and/or
aggregation of inflammatory host responses in the cranial
subdural/subarachnoid space. The outlet tube 114 is configured to remove
fluid such as local cerebrospinal fluid and/or a portion of the delivered
therapeutic drug solution from the region of the gap 110. As shown in
FIG. 3, one set of inlet and outlet tubes 112, 114 opens into each one of
the fluid exchange ports 111 in each of the gaps 110. Proximal portions
of these inlet and outlet tubes 112, 114 may be bundled together in a
bundle 116 positioned within the sheet body 102 adjacent the dorsal
surface 106 thereof, as shown in FIG. 3. The bundle 116 extends out of a
cranium of the patient to a central control unit 130, as will be
described in greater detail hereinafter. It is noted that although the
bundle 116 is depicted in FIG. 1 as a plurality of separated tubes 112,
114, the tubes 112, 114 may be encased in a single tubing arrangement
(not shown) or a double tubing arrangement as shown in FIG. 1 for ease of
implantation. Furthermore, it is noted that although the present
embodiment indicates the opening of one inlet and one outlet tube 112,
114 into each of the gaps 110, the number of either of these tubes may be
increased, thus permitting the delivery of two or more therapeutic agents
to each fluid exchange port 111 or directing the removed fluids to two or
more reservoirs separated from the cranium (e.g., into a pump reservoir
and an abdominal space). In another embodiment of the invention, the
number, lumen-size and geometric arrangement of the inlet and outlet
ports 112, 114 may vary depending on, for example, the characteristics of
the targeted cortical tissue. For example, as shown in FIG. 1, a system
100' may be formed with four sealing rings 108 formed as sealing
membranes and defining three fluid exchange ports 111 therebetween.

[0017] In another exemplary embodiment of the present invention, the
system 100 may also comprise EEG electrode contacts or neurochemical
sensors 113 to provide feedback for the cortical effects of a delivered
therapeutic agent and/or the effects of local fluid removals if these
develop. In one embodiment of the invention, the contacts may be EEG
electrodes having high frequency field potentials over approximately 100
Hz or, in another embodiment, between approximately 0.1 and 500 Hz. The
contacts 113 may be distributed over any portion of the system 100
without deviating from the scope of the present invention. In one
exemplary embodiment, the contacts 113 are positioned over predetermined
portions of the system 100 adjacent the cortical surface 20. Each of the
contacts is connected to a tubing 118 which extends alongside the bundle
116 to a position external to the cranium (e.g., to a position within the
central control unit). The contacts 113 may also be configured to monitor
levels of local neurotransmitters and metabolites in the brain. As shown
in FIG. 3, the wiring of the electrophysiological recording contacts 113
and the bundle 116 for the delivered and removed fluids are led outside
of the brain and the cranium to connect to the central control unit 130.
It is noted that although FIG. 3 depicts only predetermined positions for
contacts 113, any other positions may be employed without deviating from
the spirit and scope of the present invention.

[0018] The central control unit 130 according to the invention is formed
substantially similarly to that of U.S. Pat. No. 6,497,699 to Ludvig et
al. entitled "Hybrid Neuroprosthesis for the Treatment of Brain
Disorders" filed on Aug. 9, 2000, the entire disclosure of which is
incorporated herein by reference thereto. Specifically, the central
control unit 130 comprises a mini-pump 131 and a supporting module 132
consisting of a microcontroller, a bi-directional radiofrequency
communication system and a power supply. The mini-pump 131 is configured
as a dual mini-pump in order to provide both fluid delivery and fluid
removal to and from the subarachnoid sheet body 102. Such a dual
mini-pump has been disclosed in greater detail in the publication
entitled "Toward the Development of a Subdural Hybrid Neuroprosthesis for
the Treatment of Intractable Focal Epilepsy" to Ludvig et al. published
in 2005 in Epilepsia 46 (Suppl. 8):270 and the publication entitled
"Localized Transmeningeal Muscimol Prevents Neocortical Seizures in Rats
and Nonhuman Primates: Therapeutic Implications" to Ludvig et al.
published in 2009 in Epilepsia 50:678-693, the entire disclosures of
which are incorporated herein by reference thereto. The dual mini-pump
131 according to the present invention is configured to operate
substantially similarly to the previously disclosed mini-pump with the
exception of a modification permitting the present mini-pump 131 to
perform both fluid delivery and fluid removal in an alternating manner
through the sheet body 102. Specifically, the mini-pump 131 has a first
pump-compartment 134 directing a drug solution or therapeutic agent
solution from a delivery reservoir 136 to each of the inlet tubes 112 of
the sheet body 102. A flow of the drug solution to the sheet body 102 may
be monitored by a first flow sensor 138 provided in the control unit 130.
It is noted that although the first flow sensor 138 is depicted as housed
within the control unit 130, the first flow sensor 138 may alternately be
disposed at any position between the first pump compartment 134 and the
sheet body 102 without deviating from the scope of the invention. The
delivery reservoir 136 containing the drug solution may further be
connected to a subcutaneous refilling port 140 implanted at a
predetermined position within the patient's body. Specifically, the
refilling port 140 may be positioned, along with the control unit 130, at
a subcutaneous position so that the refilling port 140 may be accessed
via a needle or other device inserted through a patient's skin thereinto,
as those skilled in the art will understand. Furthermore, in an alternate
embodiment of the invention (not shown), the port 140 may be separated
from the control unit and connected thereto via tubing.

[0019] The mini-pump 131 further comprises a second pump compartment 142
configured to direct fluid movement in a direction opposite that of the
first pump compartment 134. Specifically, whereas the first pump
compartment directs fluid from the delivery reservoir 136 to the sheet
body 102, the second pump compartment 142 applies suction to the outlet
tubes 114 to draw fluid away from the sheet body 102 toward a CSF
collection reservoir 144 connected thereto. In one exemplary embodiment,
the second pump compartment 142 directs removed local CSF from a region
adjacent distal openings of each of the outlet tubes 114 into the CSF
collection reservoir 144. Movement of CSF and other fluids from the sheet
body 102 to the CSF collection reservoir 144 may be monitored by a second
flow-sensor 148 positioned along a length of the outlet tube 114. The CSF
collection reservoir 144 is further connected to a subcutaneous removal
port 146 positioned in a manner similar to the subcutaneous refilling
port 140 and permits the permanent removal of collected CSF and other
inflammatory products from the body via a needle or other device. The
exemplary mini-pump 131 according to the present invention permits the
delivery of fluids to and the removal of fluids from the sheet body 102
in a plurality of time intervals, some of which will be discussed in
greater detail hereinafter.

[0020] It is noted that although the control unit 130 of the present
invention is depicted as being implanted at a site remote from the
cranium, in an alternate embodiment, the subdural/subarachnoid strip 102
and the control unit 130 may both be configured and dimensioned for
implantation at a target subdural/subarachnoid site. In one exemplary
embodiment, the subdural/subarachnoid strip 102 and the control unit 130
may be formed as a single unit implantable in the subdural/subarachnoid
space. In another embodiment, the control unit 130 may be separated from
the subdural/subarachnoid strip 102 and implanted in another portion of
the cranium selected by a physician or other user, as those skilled in
the art will understand. In one exemplary embodiment, the control unit
130 is implanted at a location separated from the subdural/subarachnoid
strip 102 by approximately 30 cm, although any other placement is
envisioned without deviating from the spirit and scope of the present
invention.

[0021] In accordance with an exemplary method according to the present
invention, a craniotomy procedure is performed to remove a portion of a
skull and provide direct access to a cerebral cortex 50. One or more of
the subdural/subarachnoid sheets 102 is then inserted through the
craniotomy to rest directly on a target portion of the cerebral cortical
surface 40 and held in place by pressure applied thereto by at least the
overlying arachnoid mater 10. Once the subdural/subarachnoid sheet bodies
102 have been advanced to a target position in the cerebral cortex 50, a
bridge (not shown) formed, for example, of silicone is attached to an
unremoved portion of the skull and screwed thereto to maintain a position
thereof. As would be understood by those skilled in the art, a location
of the bridge may be chosen to lie in proximity to the treatment area
comprising the subdural/subarachnoid sheet bodies 102. The tubing 116
extends out of the craniotomy and placed along a predetermined path to
the central control unit 130 which may be implanted in a portion of the
body separate from the cerebral cortex 50. The craniotomy is then closed.

[0022] The exemplary system 100 according to the present invention is
configured to induce a sterile inflammatory host reaction to prevent the
accumulation and aggregation of inflammatory cells and molecules 16
adjacent to the distal openings of the inlet and outlet ports 112, 114.
Unless removed, these inflammatory cells and molecules 16 will obstruct
and clog the inlet and outlet ports 112, 114 within a period of
approximately two to three weeks after implantation. Once this occurs,
and all of the fluid outlet ports 114 have become obstructed along with
the subsequent clogging of the upstream fluid inlet tubes 112, the
delivery of therapeutic agents 15 through the pia mater and into the
diseased cortical tissue is no longer possible. The exemplary system and
method according to the present invention provides a solution to this
problem by periodically diluting, mobilizing and eliminating the
inflammatory tissue reaction cells and molecules 16 that invade the area
of the fluid inlet and outlet ports 114. Specifically, dilution is
provided by a periodic delivery of a medication or therapeutic agent into
each of the gaps 110 through the inlet tubes 112. The delivery of the
therapeutic agent not only serves as a treatment for underlying diseased
cortical tissue, but also, by the virtue of its solvent water, dilutes
the invading, local inflammatory products formed in the region of the
gaps 110. The dilution thus helps to prevent the aggregation of
inflammatory cells and molecules. Instead, the diluted inflammatory
products are mobilized by applying suction to each of the outlet tubes
114. The diluted and mobilized tissue reaction cells and molecules 16 are
removed from the outlet tubes 114 via a continued suction, lasting for
about 0.2-5 minutes and led into the CSF collection reservoir 144.
Removal of the inflammatory cells and molecules 16 permits drugs and
other therapeutic agents delivered through the inlet tubes 112 to freely
diffuse into the diseased cortical area and exert their therapeutic
effects without hindrance.

[0023]FIG. 4 illustrates one exemplary method for periodic subarachnoid
fluid delivery and fluid-removal cycles according to the invention. In
this method, a predetermined amount (e.g., 40 microliter) of fluid, such
as a therapeutic drug solution, is delivered to the subarachnoid space
periodically with a 12-hour pause interval 200 between successive
deliveries. The 12-hour delivery schedule alternates with fluid removals
applied periodically at 6-hour pause intervals 202 between successive
removals. As those skilled in the art will understand, a delay period 204
is applied between the first fluid delivery and the first fluid removal
so that a temporal relationship between the consecutive delivery and
removal cycles can be adjusted. In the exemplary embodiment shown, a
volume of approximately 20 microliters of fluid is withdrawn from each of
the outlet ports 114 at each removal cycle. It is noted however that the
volume of each fluid delivery and removal may be adjusted and tailored to
a patient's brain anatomy and physiology, as well as to the conditions of
the disease being treated so that each patient may require a specifically
tailored subarachnoid therapy schedule. It is therefore respectfully
submitted that the volumes and intervals disclosed herein are exemplary
only and do not limit the scope of the present invention. Any other
volumes and intervals may be employed without deviating from the spirit
and scope of the present invention.

[0024]FIG. 5 illustrates another method for periodic subarachnoid fluid
delivery and fluid removal cycles according to the present invention. The
method of FIG. 5 is substantially similar to the method described above
with respect to FIG. 4, with the exception of the timing of each of the
fluid delivery and removal cycles. Specifically, a first fluid delivery
is performed and followed at a first delay 204 of five hours by a first
fluid removal. A second fluid delivery is performed at an interval 200 of
approximately 12 hours. This delivery is immediately, or with a short
delay 206 (e.g., shorter than approximately one minute), followed by a
removal of the same amount of fluid. That is, while the periodic fluid
removals (e.g., programmed at approximately 6 hour intervals) remove only
a portion of the fluid supplied by a previous delivery, the immediate
fluid removals remove substantially the same volume of fluids from the
gaps 110 as supplied by the fluid delivery. This immediate removal
provides a flushing of the gap 110 of the fluid-exchange ports and the
lumens of the inlet and outlet tubes 112, 114, respectively, leading to
more diluting and more mobilizing effects than that achieved by the
method shown in FIG. 4. The immediate flushing is then followed by a
subsequent delivery 208 of fluids which then follows the steps disclosed
above with respect to FIG. 4. The immediate flushing may be performed at
predetermined regular intervals selected by a physician to conform to the
needs of a patient. In one embodiment, the flow of fluids into and out of
the subdural/subarachnoid space may be controlled by wirelessly
programming the control unit 130 to adjust the rate and volume of fluid
delivery and withdrawal. Specifically, the control unit 130 may comprise
a microcontroller (not shown) configured to be programmable by the
physician one of prior to implantation of the device 100 into the
patient's body and subsequent to implantation. In another embodiment of
the invention, the rates and volumes of fluid delivery and removal may be
configured to automatically adjust in response to a detection of
predetermined electrophysiological and/or neurochemical signals received
from electrodes mounted on the sheet body 102.

[0025] FIGS. 6-8 depict experimental data obtained in a monkey implanted
with the system 100 shown in FIGS. 1-3 and subjected to the periodic
fluid delivery and fluid-removal cycles of FIG. 4 over a period of three
months. In this experiment, drugs with known pharmacological actions were
delivered through the sheet body 102 to test whether the inlet and outlet
ports 112, 114 were clogged or obstructed, with the effects of the
administered drugs monitored via EEG electrode contacts 113 integrated
into the sheet body 102. The experiment was performed in a monkey
approximately three months after the implantation of the sheet body 102
over the animal's right frontal cortex and the implantation of the
control unit 130. During this post-surgical period, the delivery fluid
was saline. On the day of this experiment, the mini-pump was temporarily
modified to deliver a seizure-inducing agent (acetylcholine) through the
sheet body 102, followed by a delivery of an antiepileptic drug
(muscimol) through the same route. Traces 1 to 3 of FIG. 6 represent EEG
recordings obtained with the EEG electrodes integrated into the
subarachnoid sheet (ipsilateral recording channels 1, 2 and 3). The
fourth trace of FIG. 6 was obtained from a subdural/subarachnoid
electrode placed, during device implantation, in the left-side frontal
cortex (contralateral recording channel). Before drug delivery, the EEG
recordings showed normal patterns 300. After delivering acetylcholine
through the sheet body 102, characteristic EEG seizure patterns 302
developed in ipsilateral/treatment area channels 1, 2 and 3 but not in a
contralateral/non-treated area channel 4, as shown in FIG. 7. When
muscimol was subsequently delivered through the inlet and outlet ports
112, 114, the EEG seizure stopped within 2 min, as shown the EEG
recordings 304 of FIG. 8. The onset and cessation of the seizure activity
exhibits that the subarachnoid inlet and outlet ports 112, 114 were not
obstructed or clogged, because both acetylcholine and muscimol delivered
to the frontal cortical subarachnoid space was shown to cause clear,
localized EEG effects. Examination of the content of the collection
reservoir 144 of the mini-pump 131 proved the presence of inflammatory
cells and molecules in the removed CSF. In another monkey, not subjected
to similar periodic subarachnoid fluid delivery and fluid removal cycles
and only to periodic saline deliveries, the inlet and outlet ports 112,
114 and the tubing of the system 100 was clogged approximately three
weeks after implantation. Thus, localized drug effects, such as those
shown in FIGS. 6-8 could not be obtained unless the tubing was manually
cleansed in the anesthetized animal.

[0026] Although the present invention is designed ultimately for human
use, its applicability should not be limited to use solely on human
subjects. For example, the scope of the apparatus and methods of the
present invention includes the use of the present invention in animals as
a means to test the safety and effectiveness of therapeutic agents on the
brain in conjunction with the system of the present invention.

[0027] There are many modifications of the present invention which will be
apparent to those skilled in the art without departing from the teaching
of the present invention. The embodiments disclosed herein are for
illustrative purposes only and are not intended to describe the bounds of
the present invention which is to be limited only by the scope of the
claims appended hereto.